In lesser doses (an average cigarette yields about 2 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (50–100 mg) can be harmful.[10][11][12] This stimulant effect is a major contributing factor to the addictive properties of tobacco smoking.

Studies suggest that when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.[23] This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a higher level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer with increasing dosages and use, a phenomenon described by Paul Nesbitt in his doctoral dissertation[24] and subsequently referred to as "Nesbitt's paradox".[25]

The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence.

Studies have found that these therapies increase the chance of success of quitting by 50 to 70%,[26] though reductions in the population as a whole has not been demonstrated.[27]

Nicotine is frequently used for its performance enhancing effects on cognition, alertness and focus.[28][29] It is second only to caffeine as the most widely used nootropic in the world.[citation needed]

Nicotine is not regarded as a carcinogen.[35] The IARC has not evaluated nicotine in its standalone form or assigned it to an official carcinogen group. While no epidemiological evidence supports that nicotine acts as a carcinogen in the formation of human cancer, research over the last decade has identified nicotine's indirect involvement in cancer formation in animal models and cell culture.[36][37][38] Nicotine increases cholinergic signalling (and adrenergic signalling in the case of colon cancer[39]), thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-LOX, and EGF. Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization.[40][41] In one study, nicotine administered to mice with tumors caused increases in tumor size (twofold increase), metastasis (nine-fold increase), and tumor recurrence (threefold increase).[42]N-Nitrosonornicotine (NNN), classified by the IARC as a Group 1 carcinogen, has been shown to form in vitro in amounts less than 0.01% the active substance, when human saliva is incurbated with nornicotine.[43]

In pregnancy, a 2013 review noted that "nicotine is only 1 of more than 4000 compounds to which the fetus is exposed through maternal smoking. Of these, ∼30 compounds have been associated with adverse health outcomes. Although the exact mechanisms by which nicotine produces adverse fetal effects are unknown, it is likely that hypoxia, undernourishment of the fetus, and direct vasoconstrictor effects on the placental and umbilical vessels all play a role. Nicotine also has been shown to have significant deleterious effects on brain development, including alterations in brain metabolism and neurotransmitter systems and abnormal brain development." It also notes that "abnormalities of newborn neurobehavior, including impaired orientation and autonomic regulation and abnormalities of muscle tone, have been identified in a number of prenatal nicotine exposure studies" and that there is weak data associating fetal nicotine exposure with newborn facial clefts, and that there is no good evidence for newborns suffering nicotine withdrawal from fetal exposure to nicotine.[44]

Difficulty concentrating and deficits in task performance are symptoms of nicotine withdrawal. These symptoms begin as soon as 30 minutes after tobacco cessation begins, and can last for several weeks.[46]

Nicotine appears to have significant performance enhancing effects, particularly in fine motor skills, attention, and memory. These beneficial cognitive effects may play a role in the initiation and maintenance of tobacco dependence.[46]

The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 30–60 mg (0.5–1.0 mg/kg) can be a lethal dosage for adult humans.[10][50] However the widely used human LD50 estimate of 0.5–1.0 mg/kg was questioned in a 2013 review, in light of several documented cases of humans surviving much higher doses; the 2013 review suggests that the lower limit causing fatal outcomes is 500–1000 mg of ingested nicotine, corresponding to 6.5–13 mg/kg orally.[12] Nevertheless, nicotine has a relatively high toxicity in comparison to many other alkaloids such as caffeine, which has an LD50of 127 mg/kg when administered to mice.[51]

It is unlikely that a person would overdose on nicotine through smoking alone, the US Food and Drug Administration (FDA) states in 2013 "There are no significant safety concerns associated with using more than one OTCNRT at the same time, or using an OTC NRT at the same time as another nicotine-containing product—including a cigarette."[52] Spilling a high concentration of nicotine onto the skin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermal contact.[53]

Nicotine also activates the sympathetic nervous system,[67] acting via splanchnic nerves to the adrenal medulla, stimulating the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and noradrenaline) into the bloodstream. Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or due to the irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals. However, further research is warranted before a definite conclusive link can be inferred.[68]

The amount of nicotine absorbed by the body from smoking can depend on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. However, it has been found that the nicotine yield of individual products has only a small effect (4.4%) on the blood concentration of nicotine,[73] suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation".

Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine. Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.[74] Under some conditions, other substances may be formed such as myosmine.[75]

Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory with a specific rotation of [α]D = –166.4° ((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less active than (–)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.[79] The salts of (+)-nicotine are usually dextrorotatory. The hydrochloride and sulphate salts become optically inactive if heated in a closed vessel above 180 °C.[80]

On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (vitamin B3), and methylamine.[80]

Nicotine is a natural product of tobacco, occurring in the leaves in a range of 0.5 to 7.5% depending on variety.[81] Nicotine also naturally occurs in smaller amounts in plants from the family Solanaceae (such as potatoes, tomatoes, and eggplant).[82]

The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ1-pyrrollidium cation.[83][84] Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ1-pyrrollidium cation.

The NAD pathway in the genus nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoriboxyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.[citation needed]

The N-methyl-Δ1-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.[citation needed]

The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ1-pyrrollidium cation to form enantiomerically pure (–)-nicotine.[85]

Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids.[86][87] Nicotine use is not regulated in competitive sports programs.[88]

Tobacco was introduced to Europe in 1559, and by the late 17th century, it was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals.[9]

In 2008, the EPA received a request, from the registrant, to cancel the registration of the last nicotine pesticide registered in the United States.[92] This request was granted, and since 1 January 2014, this pesticide has not been available for sale.[93]

The nicotine content of popular American-brand cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.78% per year between the years of 1998 and 2005.[101]

While acute/initial nicotine intake causes activation of nicotine receptors, chronic low doses of nicotine use leads to desensitisation of nicotine receptors (due to the development of tolerance) and results in an antidepressant effect, with research showing low dose nicotine patches being an effective treatment of major depressive disorder in non-smokers.,[102] However the original research concluded that: "Nicotine patches produced short-term improvement of depression with minor side effects. Because of nicotine's high risk to health, nicotine patches are not recommended for clinical use in depression."[103]

Though tobacco smoking is associated with an increased risk of Alzheimer's disease,[104] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.[105]

Research into nicotine's most predominant metabolite, cotinine, suggests that some, if not most, of nicotine's psychoactive effects may actually be mediated by complex interactions with cotinine, or perhaps even by cotinine alone rather than strictly by nicotine as conventionally thought.[106][107]

Little research is available in humans but animal research suggests there is potential benefit from nicotine in Parkinson's disease.[108]

There is tentative evidence that nicotinamides may improve depression.[109]

^ abcRuffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am J Drug Alcohol Abuse40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID25083822. The knowledge of ΔFosB induction in chronic drug exposure provides a novel method for the evaluation of substance addiction profiles (i.e. how addictive they are). Xiong et al. used this premise to evaluate the potential addictive profile of propofol (119). Propofol is a general anaesthetic, however its abuse for recreational purpose has been documented (120). Using control drugs implicated in both ΔFosB induction and addiction (ethanol and nicotine), ...

Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a ‘‘molecular switch’’ (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124).

^Gause, G. F. (1941). "Chapter V: Analysis of various biological processes by the study of the differential action of optical isomers". In Luyet, B. J. Optical Activity and Living Matter. A series of monographs on general physiology 2. Normandy, Missouri: Biodynamica.